Rosiglitazone decreases blood pressure and renal injury in a female mouse model of systemic lupus erythematosus

Abstract

-Women with systemic lupus erythematosus (SLE) exhibit a high prevalence of hypertension and renal injury. Rosiglitazone (Rosi), a peroxisome proliferator activator receptor gamma (PPAR␥) agonist, has renal protective and antihypertensive effects. We tested whether Rosi ameliorates hypertension and renal injury in a female mouse model of SLE (NZBWF1). Thirty-week-old SLE and control (NZW/LacJ) mice (n Ն 6/group) were fed Rosi (5 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 in standard chow) or standard chow for 4 wk. SLE mice had increased blood pressure (BP in mmHg) compared with controls (139 Ϯ 4 vs. 111 Ϯ 4, P Ͻ 0.05). Rosi treatment lowered BP in SLE mice (127 Ϯ 4, P Ͻ 0.05) but not in controls (111 Ϯ 4). Urinary albumin (g/mg creatinine) was increased in SLE mice compared with controls (12,396 Ϯ 6,525 vs. 50 Ϯ 6) and reduced with Rosi treatment (148 Ϯ 117). Glomerulosclerosis (% of glomeruli with sclerosis) was reduced in Rosi-treated SLE mice (4.2 Ϯ 1.6 vs. 0.4 Ϯ 0.3, P Ͻ 0.05). Renal monocyte/ macrophage numbers (cell number/1,320 points counted) were reduced in SLE mice treated with Rosi (32.6 Ϯ 11.0 vs. 10.6 Ϯ 3.6, P Ͻ 0.05) but unchanged in controls (3.7 Ϯ 1.6 vs. 3.7 Ϯ 2.0). Renal osteopontin expression, a cytokine-regulating macrophage recruitment, was reduced in Rosi-treated SLE mice. Urinary endothelin (in pg/mg creatinine) was increased in SLE mice compared with controls (1.9 Ϯ 0.59 vs. 0.6 Ϯ 0.04, P Ͻ 0.05) and reduced in SLE mice treated with Rosi (0.8 Ϯ 0.11, P Ͻ 0.05). PPAR␥ protein expression in the renal cortex was significantly lower in SLE mice compared with controls and was unaffected by Rosi. These data suggest that Rosi may be an important therapeutic option for the treatment of SLE hypertension and renal injury. lupus; inflammation; endothelin; glomerulosclerosis; proliferator activated receptor gamma SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) is a chronic autoimmune inflammatory disorder that has a strong predilection for women during their reproductive years. The hallmark of the disease is the production of autoantibodies such as antinuclear antibodies, and more specifically anti-double-stranded DNA (antidsDNA) antibodies. Accumulating evidence indicates that the major cause of death among patients with SLE is cardiovascular disease (17,22,23,26). Indeed, studies have reported that women with SLE are at a 50-fold greater risk for developing cardiovascular disease independent of traditional Framingham Heart Study risk factors (35). One of the major factors contributing to the progression of cardiovascular disease is increased arterial pressure. Importantly, SLE is associated with a high incidence of hypertension (1, 41, 56).The kidneys are prominently affected during SLE in the form of immune complex glomerulonephritis. This occurs in greater than 50% of patients with SLE (18) and is caused, in part, by circulating anti-dsDNA antibody-mediated formation of immune complexes (51). Few advances have been made toward the treatment of SLE and the associated nephritis and hypertension in the past 40 years. Patients with SL...

Blood pressure and renal hemodynamic responses to acute angiotensin II infusion are enhanced in a female mouse model of systemic lupus erythematosus

“…The pivotal role for the kidney in the long-term control of blood pressure is well known and a decreased renal blood flow can mechanistically contribute to the hypertensive shift in the pressure natriuresis relationship. Importantly, prevalent hypertension contributes to the greater cardiovascular risk in patients with SLE (25,33,35,51), and we previously demonstrated that, similar to humans with SLE, NZBWF1 mice develop hypertension (40,41,53,54). Under the current experimental conditions, the hypertension that is observed in conscious animals is largely muted as a result of the anesthesia.…”

“…Renal cortical protein expression of AT1R, ANG II receptor type-2 (AT2R) and renin were determined using standard Western blot analysis methods, as previously described (53,54). Rabbit polyclonal anti-AT1R antibody (1:500; Alomone Laboratories, Jerusalem, Israel), rabbit polyclonal anti-AT2R antibody (1:500; Alomone Laboratories), goat polyclonal anti-renin (1:250; Santa Cruz Biotechnology, Santa Cruz, CA) and mouse anti-␤-actin (1:5,000; Abcam, Cambridge, MA) were used.…”

Rosiglitazone Attenuates Endothelin-1–Induced Vasoconstriction by Upregulating Endothelial Expression of Endothelin B Receptor

“…More recently, it was demonstrated that rosiglitazone treatment decreased blood pressure and was effective in preventing the progression of renal injury in deoxycorticosterone acetate-salt hypertension through reducing the overexpression of ET-1 in the kidney 21 and that rosiglitazone decreased blood pressure and renal injury in a female mouse model of systemic lupus erythematosus accompanied by a reduction of urinary ET. 22 The mechanisms underlying the vasoprotective effects of TZDs remain largely unknown. The present study clearly shows that 24-hour treatment with rosiglitazone suppressed ET-1-induced and ET A R-mediated contraction only in rings with endothelium.…”

“…22,25 The prevalence of atherosclerosis and hypertension in diabetic patients is approximately twice compared with that of nondiabetics. 26 Conversely, the chance of developing type 2 diabetes mellitus in atherosclerosis and hypertensive individuals is also 2-to 4-fold higher than that in normotensive individuals.…”

LXR, PPAR<i>γ</i>, and PPAR<i>δ</i> Agonists Are Not Sufficient to Demonstrate Therapeutic Potential against Mouse Model of Systemic Lupus Erythematosus

“…Peroxisome proliferator-activated receptor γ (PPARγ) agonists are widely prescribed for the pharmacological treatment of type 2 diabetes by their insulin-sensitizing properties. PPARγ agonists also exert anti-inflammatory and immunomodulatory effects, and the beneficial impacts of rosiglitazone were reported for the amelioration of the autoantibody production, renal disease, and atherosclerosis in MRL-lpr mice depending on the induction of adiponectin [1] and also in NZBWF1 mice [2]. SLE is associated with increased circulating apoptotic autoantigens and increased type I interferon (IFN) signaling which simulate the production of autoantibody including anti-dsDNA antibodies [3].…”